- A class of triacylamine derivatives containing 1,8-naphthalimide and preparation method and use thereof
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The present invention provides a class of triacylamine derivatives of 1,8-naphthalimide and preparation methods and uses thereof, the present invention relates to a triacylamine derivative of 1,8-naphthoimide, which has a general formula of chemical struc
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Paragraph 0010; 0025-0026
(2022/01/12)
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- Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27
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GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called “Super-Conserved Receptors Expressed in the Brain” (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.
- Blavier, Jeremy,Charles, Ma?lle,Hanson, Julien,Kronenberger, Thales,Laschet, Céline,Müller, Christa E.,Pillaiyar, Thanigaimalai,Rosato, Francesca,Wozniak, Monika
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- Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
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An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
- Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
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supporting information
p. 17887 - 17896
(2020/08/19)
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- Crystal engineering of hand-twisted helical crystals
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A strategy is outlined for the design of hand-twisted helical crystals. The starting point in the exercise is the one-dimensional (1D) plastic crystal, 1,4-dibromobenzene, which is then changed to a 1D elastic crystal, exemplified by 4-bromophenyl 4'-chlorobenzoate, by introduction of a molecular synthon -O-CO-in lieu of the supramolecular synthon Br···Br in the precursor. The 1D elastic crystals are next modified to two-dimensional (2D) elastic crystals, of the type 4-bromophenyl 4'-nitrobenzoate where the halogen bonding and C-H· · ·O hydrogen bonding are well-matched. Finally, varying the interaction strengths in these 2D elastic crystals gives plastic crystals with two pairs of bendable faces but without slip planes. Typical examples are 4-chlorophenyl and 4-bromophenyl 4'-nitrobenzoate. This type of 2D plasticity represents a new type of bendable crystals in which plastic behavior is seen with a fair degree of isotropic character in the crystal packing. The presence of two sets of bendable faces, generally orthogonal to each other, allows for the possibility of hand-twisting of the crystals to give grossly helical morphologies. Accordingly, we propose the name hand-twisted helical crystals for these substances.
- Saha, Subhankar,Desiraju, Gautam R.
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supporting information
p. 1975 - 1983
(2017/02/15)
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- Dibenzo[b,f][1,4]oxazepines and dibenzo[b,e]oxepines: Influence of the chlorine substitution pattern on the pharmacology at the H1R, H4R, 5-HT2AR and other selected GPCRs
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Inspired by VUF6884 (7-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine), reported as a dual H1/H4 receptor ligand (pKi: 8.11 (human H1R (hH1R)), 7.55 (human H4R (hH4R))), four known and 28 new oxazepine and related oxepine derivatives were synthesised and pharmacologically characterized at histamine receptors and selected aminergic GPCRs. In contrast to the oxazepine series, within the oxepine series, the new compounds showed high affinity to the hH1R (pKi: 6.8–8.7), but no or moderate affinity to the hH4R (pKi: ≤ 5.3). For one oxepine derivative (1-(2-Chloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine), the enantiomers were separated and the R-enantiomer was identified as the eutomer at the hH1R (pKi: 8.83 (R), 7.63 (S)) and the guinea-pig H1R (gpH1R) (pKi: 8.82 (R), 7.41 (S)). Molecular dynamic studies suggest that the tricyclic core of the compounds is bound in a similar mode into the binding pocket, as described for doxepine in the hH1R crystal structure. Moreover, docking studies of all oxepine derivatives at the hH1R indicate that the oxygen and the position of the chlorine in the tricyclic core determines, if the R- or the S-enantiomer is the eutomer. For some of the oxazepines and oxepines the affinity to other aminergic GPCRs is in the same range as to hH1R or hH4R, thus, those compounds have to be classified as dirty drugs. However, one oxazepine derivative (3,7-Dichloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine was identified as dual hH1/h5-HT2A receptor ligand (pKi: 9.23 (hH1R), 8.74 (h5-HT2AR), ≤7 at other analysed GPCRs), whereas one oxepine derivative (1-(3,8-Dichloro-6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-methylpiperazine) was identified as selective hH1R antagonist (pKi: 8.44 (hH1R), ≤6.7 at other analyzed GPCRs). Thus, the pharmacological results suggest that the oxazepine/oxepine moiety and additionally the chlorine substitution pattern toggles receptor selectivity and specificity.
- Naporra, Franziska,Gobleder, Susanne,Wittmann, Hans-Joachim,Spindler, Julia,Bodensteiner, Michael,Bernhardt, Günther,Hübner, Harald,Gmeiner, Peter,Elz, Sigurd,Strasser, Andrea
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p. 610 - 625
(2016/10/12)
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- Site-Selective Silylation of Aliphatic C-H Bonds Mediated by [1,5]-Hydrogen Transfer: Synthesis of α-Sila Benzamides
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The first example of site-selective silylation of C(sp3)-H bonds mediated by a [1,5]-hydrogen transfer is reported. This reaction occurs selectively at the α-position of benzamides with a combination of tert-butylmagnesium chloride and a catalytic amount of 4,4′-di-tert-butylbipyridine (dtbpy) ligand and provides a facile route for the creation of biologically interesting α-sila benzamides. Late-stage functionalization of the incorporated silyl moieties facilitates the synthesis of N-formyl, cis-enamine, β-hydroxyl, amino, and pyrrole-containing derivatives.
- Liu, Pei,Tang, Jinghua,Zeng, Xiaoming
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supporting information
p. 5536 - 5539
(2016/11/17)
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- AMINE COMPOUND AND USE THEREOF FOR MEDICAL PURPOSES
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The present invention provides a compound represented by the following formula (I): wherein each symbol is as described in the DESCRIPTION, which has a superior peripheral blood lymphocyte decreasing action, and is useful for the treatment or prophylaxis of autoimmune diseases; prophylaxis or suppression of resistance or acute rejection or chronic rejection of transplantation of organ or tissue; treatment or prophylaxis of graft-versus-host (GvH) disease due to bone marrow transplantation; or treatment or prophylaxis of allergic diseases.
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Paragraph 0247-0248
(2015/03/16)
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- Analogues of fenarimol are potent inhibitors of trypanosoma cruzi and are efficacious in a murine model of chagas disease
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We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC50s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
- Keenan, Martine,Abbott, Michael J.,Alexander, Paul W.,Armstrong, Tanya,Best, Wayne M.,Berven, Bradley,Botero, Adriana,Chaplin, Jason H.,Charman, Susan A.,Chatelain, Eric,Von Geldern, Thomas W.,Kerfoot, Maria,Khong, Andrea,Nguyen, Tien,McManus, Joshua D.,Morizzi, Julia,Ryan, Eileen,Scandale, Ivan,Thompson, R. Andrew,Wang, Sen Z.,White, Karen L.
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supporting information; experimental part
p. 4189 - 4204
(2012/07/27)
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- Synthesis and anti-cancer, anti-metastatic evaluation of some new fluorinated isocoumarins and 3,4-dihydroisocoumarins
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Synthesis of some fluorinated isocoumarins and 3,4-dihydroisocoumarins is reported. Structures of the synthesized compounds were confirmed by spectral and elemental analysis. All the synthesized compounds were evaluated for their antimetastatic activity and anti-cancer activity against breast cell line (MCF-7). Among all the tested compounds 3h [3-(3′,4′-difluorophenyl) isocoumarin] has shown excellent antimetastatic activity, however the growth inhibitory response of the tested compounds [3a-h, 4a-h, 5e-h, 6a-h and 7a, c, d] for MCF-7 human breast carcinoma cell line was moderate at higher concentrations (100-400 μM) and negligible at lower concentrations.
- Abid, Obaid-Ur-Rahman,Khalid, Muhammad,Hussain, Muhammad T.,Hanif, Muhammad,Qadeer, Ghulam,Rama, Nasim H.,Kornienko, Alexander,Khan, Khalid M.
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experimental part
p. 240 - 245
(2012/05/04)
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- VIRAL POLYMERASE INHIBITORS
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Compounds of formula I: wherein X, R2, R3, R3a, R3b,R5 and R6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.
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Page/Page column 97
(2009/07/18)
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- Synthesis and evaluation of a new series of substituted acyl(thio)urea and thiadiazolo [2,3-a] pyrimidine derivatives as potent inhibitors of influenza virus neuraminidase
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A series of substituted acyl(thio)urea and 2H-1,2,4-thiadiazolo [2,3-a] pyrimidine derivatives were prepared and both of their cell culture and enzymatic activity toward influenza virus were tested. Their in vitro neuraminidase inhibitory activities were in good agreement with the corresponding activities in cultured cells and they were evaluated as potent neuraminidase inhibitors. Of the analogues that demonstrated IC50s 0.1 μM, 16 and 60 were further investigated as candidates with the most potential for future development. The molecular docking work of the representative compound was described to provide more insight into their mechanism of action and further rationalize the observations of this new series herein, which represents a novel class of highly potent and selective inhibitors of influenza virus.
- Sun, Chuanwen,Zhang, Xiaodong,Huang, Hai,Zhou, Pei
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p. 8574 - 8581
(2008/02/07)
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- CRYSTALLINE FORM OF 2-{4-‘3-(4-CHLORO-2-FLUOROPHENYL)-4-PYRIMIDIN-4-YL-1H-PYRAZOL-5-YL!PIPERIDIN-1-YL}-2-OXOETHANOL
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Crystalline form of the p38 kinase inhibitor 2-{4-[3-(4-chloro-2-fluorophenyl)-4-pyrimidin-4-yl-lH-pyrazol-5-yl]piperidin-1-yl}-2-oxoethanol can be used, is provided. The crystalline form is a hydrated crystalline form. Also provided are combinations and
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Page/Page column 21-22
(2008/06/13)
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- PROCESS FOR MAKING SUBSTITUTED PYRAZOLES
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This invention is directed generally to a process for making substituted pyrazoles, The substituted pyrazole corresponds in structure to formula 9 : wherein Q, R4,R3A, R3B, R3C, R3D, and R3E/sup
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Page/Page column 38-39
(2008/06/13)
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- N-Aroyloxylthioxo-naphthalimides as DNA photocleavers of aroyloxyl oxygen radicals: Synthesis, evaluation, and substituents' effect
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Novel N-Aroyloxylthioxo-naphthalimides as highly efficient 'time-resolved' DNA photocleavers of aroyloxyl radicals type were designed and synthesized. The substituents at the aroyloxyl moiety have an important and unusual influence on the DNA photocleavage, and DNA photodamages of the compounds were unusually not depended on the electronic effects of substituents on the corresponding oxygen-centered radicals. With AM1 semi-empirical quantum calculation, it was found that their photocleaving activities were correlated with the densities of electron clouds on the N-O bonds in the triplet state. N-(m-Dichloro-benzoyloxy) -thioxo-naphthalimide could photodamage DNA effectively at less than the concentration of 2μM.
- Xu, Yufang,Huang, Xiayu,Qian, Xuhong,Yao, Wei
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p. 2335 - 2341
(2007/10/03)
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- Amino acid derivatives
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Described herein are compounds having the general formula: wherein: Ar1 and Ar2 are independently selected aryl groups, optionally substituted with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, alkanoyl, aralkyl, aralkyloxy
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